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Nutritional support in early Alzheimer’s disease: what, why and when? Laus Broersen, PhD Senior Neuroscientist Nutricia Research, Advanced Medical Nutrition.

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Presentation on theme: "Nutritional support in early Alzheimer’s disease: what, why and when? Laus Broersen, PhD Senior Neuroscientist Nutricia Research, Advanced Medical Nutrition."— Presentation transcript:

1 Nutritional support in early Alzheimer’s disease: what, why and when? Laus Broersen, PhD Senior Neuroscientist Nutricia Research, Advanced Medical Nutrition Utrecht, The Netherlands

2 AD specific nutrient requirement to meet the increased demand for synapse formation 3 Souvenaid addresses the nutritional need to support increased synapse formation in patients with AD 4 Lower nutrient intake, uptake and metabolism Lower brain nutrient levels AD-induced compromised nutrient availability 1 A Lower blood nutrient levels B C Patients with AD show lower number of brain synapses In AD a specific need exists to enhance synapse formation Patients with AD show lower level of neuronal membranes 2 A B Membrane and synapse formation dependent on nutrient availability C AD specific nutritional needs for membrane and synapse formation

3 Synapse loss is structural basis of functional deficits in AD Synapse loss in AD is confirmed in >30 publications Reduced number of synapses ControlMCIAD * -13%-44% # synapses dentate gyrus (x10 10 )

4 ControlAD Einstein et al (1994) J Neurosci ControlAD Mavroudis et al (2010) Am J Alz Dis oth Dement ControlAD Tsamis et al (2010) Curr Alzheim Res ControlAD Catala et al (1988) Hum Neurobiol Loss of dendritic spines in AD

5 Decreased brain phospholipids in AD indicates disrupted membrane integrity 4. Conclusions “… Phospholipids provide an optimal membrane environment for protein interactions, trafficking and function. There is increasing evidence that phospholipid changes occur during pathogenic processes in Alzheimer’s disease. …”

6 The Kennedy pathway for biosynthesis of neuronal membrane Membranes are main constituents of synapses Axon neurite dendritic spine Neurite Dendritic spine Axon terminal Phosphocholine CDP-choline Phosphatidylcholine New neuronal membrane Phospholipids Choline Uridine Omega-3 fatty acids Dietary precursor control of neural membrane synthesis

7 The Kennedy pathway for biosynthesis neuronal membrane Kennedy & Weiss (1956) J Biol Chem Phosphocholine CDP-choline Phosphatidylcholine New neuronal membrane Phospholipids Choline Uridine Omega-3 fatty acids Dietary precursor control of neural membrane synthesis

8 Brain phospholipids (PE) (nmol/mg protein) UMP DHA *** * Control Wurtman et al (2005, 2006) Brain Res Dietary precursors can be rate-limiting: Synergy between dietary precursors

9 Dietary precursors increase membrane dominant structures: Dendritic spines Sakamoto et al (2007) Brain Res Spine Density hippocampus (for 50µM) Control (choline) UMP UMP DHA DHA ** *

10 B-vitamins: cofactors for endogenous production of membrane precursors PEMT = phosphatidylethanolamine-N-methyltransferase

11 B vitamins increase choline B vitamins dose-dependently increase DHA van Wijk et al (2012) Nutr Metabol van Wijk et al (2011) Br J Nutr Precursor availability: B-vitamins increase plasma choline and DHA

12 Nutritional precursors and cofactors: enhanced availability by Fortasyn Connect Synapses are continuously being remodeled Synapses are part of the neuronal membrane Membranes consist of phospholipids Phospholipid synthesis depends on the presence of uridine, choline and DHA B-vitamins enhance precursor bioavailability Antioxidants protect the neuronal membrane and maintain its integrity, stability and function

13 Key phenomena being studied Increase precursor supply Co-factors increase precursor availability Increase phosphatide / membrane synthesis Improved membrane composition Increase neurite outgrowth Increase connectivity (grey and white matter integrity) Increase synaptic proteins Increase synaptic contacts Increase neurotransmission (ACh synthesis, release, receptors) Synergy between nutrients Reduced abeta production/plaque formation/toxicity Reduced neurodegeneration (immunoreactivty & NAA) Improve learning & memory / behavior Confirmed & Published Fortasyn Connect Nutrient combinations ,26 24,26,28 19,23 19,21,28 19,22,23,29  19,22,23 19,22,            18 1,2 2,5,8,11,17 11,23 6,7 8 5,7,8,17 2,5,7,8 3,4            2,6,9,10 11, ,12 Precursors and cofactors enhance synapse formation and function – basic science data 1.Cansev (2005) Brain Res 2.Ulus (2006) Cell Mol Neurobiol 3.Van Wijk (2011) Br J Nutr 4.Van Wijk (2012) Nutr Metab 5.Wurtman (2006) Brain Res 6.Wang (2005) J Mol Neurosci 7.Pooler (2005) Neuroscience 8.Sakamoto (2007) Brain Res 9.Farkas (2002) Brain Res 10.Wang (2007) Brain Res 11.Kariv-Inbal (2012) JAD 12.Grimm (2011) JBC 13.Teather (2003) PNBP 14.de Wilde (2003) Brain Res 15.de Wilde (2002) Brain Res 16.de Bruin (2003) J Learn Mem 17.Holguin (2008) BehavBrainRes 18.van Wijk (2014) JAD 19.de Wilde (2011) J Alz Dis 20.Cansev (2012) data on file 21.Cansev (2013) data on file 22.Jansen (2013) PLOS ONE 23.Broersen (2013) J Alz Dis 24.Savelkoul (2012) AAIC 25.Zerbi (2013) Neurobiol Aging 26.Savelkoul (2011) ADPD 27.Verheijen (2012) data on file 28.Savelkoul (2012) J Neurochem 29.Jansen (2013) Brain Struc Fun 30.Koivisto (2013) in press 31.Wiesmann (2013) JAD

14 AD risk and nutrient intake AD incidence by diet tertile Scarmeas et al (2006) Ann Neurol Observational studies suggest a link between Mediterranean diet & AD risk, but data not fully consistent Mediterranean diet: High vegetables, legumes, fruits, and cereals High unsaturated fatty acids Low saturated fatty acids Moderately high fish Low-to-moderate dairy Low meat and poultry Regular but moderate amount of ethanol, primarily in the form of wine and generally, during meals Scarmeas et al, Ann Neurol, 2006; Psaltopoulou et al, Public Health Nutr, 2008; Feart et al, JAMA, 2009; Cherbuin et al, Am J Geriatr Psychiatry, 2011; Tangney et al, Am J Clin Nutr, 2011

15 Systematic review and meta-analysis on nutrient availability in AD According to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines Analyses by independent statisticians

16 Systematic review and meta-analysis of literature: Lower plasma levels of precursors & cofactors in AD % Cognitive Intact elderly Plasma nutrient status in AD Meta-analyses, systematic review and observations studies DHAEPA * * Meta-analyses Lin (2012) JCP 6 studies9 studies Vit B6 Choline Meta-analyses data on file *** 37 studies31 studies 20 studies 8 studies FolateVit B12Vit C Vit E Meta-analyses Lopes da Silva (2013) Alz Dement 11 studies Selenium * Systematic review Loef (2011) JAD 2 studies Uridine *1*1 *2*2 1:Trushina (2013) PLOS 2:Olde Rikkert (2013)ADPD *

17 Lower nutrient status preceding classic protein energy malnutrition Mi et al (2013) Nutrition Epidemiological relate dietary patterns with AD risk

18 Increased nutritional need cannot be met by the regular diet Development of Souvenaid: addressing AD specific requirements Stimulating synapse formation requires specific nutrients Lower Nutrient status & altered nutrient metabolism HYPOTHESIS: Souvenaid successfully addresses an unmet nutritional need in people with AD by increasing their intake of these dietary precursors and co-factors Uridine (UMP), Omega-3 fatty acids, Phosholipids & Choline, B-Vitamins, Antioxidants 400 mg Choline 300 mg EPA 625 mg UMP 3 mcg Vit B12 1 mg Vit B6 80 mg Vit C 1200 mg DHA 400 mcg Folate 106 mg Phospholipids 60 mcg Selenium 40 mg Vit E

19 Prodromal ADModerate AD ADAS-cog MMSE 14-24, stable on AD drugs NTB + MRI / CSF MMSE ≥ 24, drug-naïve LipiDiDietMRS studyMEG study Souvenir IISouvenir IS-ConnectOpen Label NTB + EEG MMSE ≥ 20, drug-naïve WMS-r & ADAS-cog MMSE 20-26, drug-naïve Souvenir I received funding from NL STW Souvenir II receives funding from the NL Food & Nutrition Delta project, FND N°10003 LipiDiDiet is funded by the EU FP7 project LipiDiDiet, Grant Agreement N° NL-Enigma funded by NWO NIHC project, N° Safety + Compliance + NTB 31 P and 1 H-MRS MMSE ≥ 20, drug-naïve MEG + EEG +NTB MMSE ≥ 20, drug-naïve Mild AD Souvenaid Clinical Development 18 FDG-PET MMSE ≥ 20, drug-naïve NL-Enigma

20 S-Connect study: mild to moderate AD on AD medication Principle investigators: David Bennett and Raj Shah, Rush, Chicago Multi-centre (48 sites in the US), randomized, controlled trial Intervention 24 weeks Primary outcome: – ADAS-cog-11 t≤-3 t= wks n=527 Souvenaid (n=265) Control (n=262) Outcome parameters Values are mean ±SD, unless stated otherwise Shah et al (2013) Alz Res Ther Baseline Characteristics Control (n = 262) Active (n = 265) Age (y)76.9 (8.2)76.6 (8.2) Sex: males (n[%])127 (48.5%)126 (47.5%) Years of education on top of primary school 6.4 (3.5)6.7 (3.6) Total MMSE score19.3 (3.0)19.5 (3.2) Duration AD since diagnosis (months) 34.9 (29.6)32.7 (25.0) Acetylcholinesterase inhibitors243 (92.7%)251 (94.7%) NMDA antagonist170 (64.9%)177 (66.8%) BMI (kg/m2)26.64 (4.56)26.19 (4.51) No significant effect (p=0.513) during 24 weeks ITT, MMRM, data are mean ±SE

21 Souvenir I: Proof of concept study in drug-naive mild AD Multi-country (NL, Bel, Ger, UK, US), randomized, controlled trial Intervention 12 weeks (+ optional 12 wk extension) Co-primary outcomes: – WMS-r delayed verbal recall – ADAS-cog-13 t≤-3 t= wks n=212 Souvenaid (n=106) Control (n=106) Outcome parameters Baseline characteristics Control (n = 106) Souvenaid Sex (male/female; counts)52 / 5454 / 52 Age (y)73.3 ± ± 7.2 BMI (kg/m2)26.2 ± ± 4.8 Years of education on top of primary school 6.0 ± ± 3.9 Days since AD diagnosis (median) 31.5 (0–1036) 30.0 (0–1932) Total MMSE score24.0 ± ± 2.7 Values are mean ±SD, unless stated otherwise Scheltens et al (2010) Alzh Dement Significantly more responders after 12 weeks (p=0.021) Change in WMS-r delayed verbal recall score

22 Souvenir II study: drug-naive mild AD Multi-country (NL, Ger, Bel, Fr, It, Sp), randomized, controlled trial Intervention 24 weeks Primary outcome: Memory Domain NTB (z-score): – RAVLT immediate, delayed, recognition and VPA immediate and delayed t≤-3 t= wks n=259 Souvenaid (n=130) Control (n=129) Outcome parameters Values are mean ±SD, unless stated otherwise Scheltens et al (2012) J Alzheimers Dis Baseline characteristics Baseline characteristicsControl (n = 129) Souvenaid (n = 130) Age (y) 73.2 (8.4)74.4 (6.9) Sex: males (n[%]) 64 (49.6)68 (52.3) Years of education on top of primary school 6.6 (4.6)6.5 (4.8) Total MMSE score 25.1 (2.9)25.1 (2.8) Duration AD since diagnosis (months) (median[range]) 2.0 ( )1.0 ( ) BMI (kg/m2) 26.7 (4.2)26.1 (4.1) Significantly improved memory (p=0.023) Memory domain score (z-score) of NTB

23 Electrical activity at the synapse – EEG biomarker for functional connectivity Signal strength Peak Frequency PLI Functional connectivity Phase Lag Index (PLI) HealthyAD Network Organization Clustering / Path length P=0.019P=0.011P=0.009 Scheltens et al (2012) J Alzheimers Dis; de Waal et al (2014) PlosOne

24  Mapstone et al. identified a biomarker panel of 10 plasma lipids that can predict conversion from cognitive healthy to MCI/AD within 2–3 years with >90% accuracy  Changes may reflect the breakdown of neuronal membranes  Highly publicitized findings  set of 10 plasma lipids, including 8 phospholipids  levels are lower in converters and MCI/AD subjects

25 Souvenaid increases levels of the biomarker phospholipids  Baseline and 24-week plasma samples from the Souvenir II study  Drug-naïve patients with very mild AD  Polar lipid profile  By providing nutrients which normally rate-limit phospholipid synthesis Souvenaid can: modify a biomarker profile reflecting disturbed phospholipid metabolism be useful in asymptomatic subjects with plasma lipid biomarker profiles predictive for conversion to AD 5 / 7 measured phospholipids reported by Mapstone significantly increased by Souvenaid * P<0.001; Souvenaid vs. Control using ANCOVA

26 Prodromal ADModerate AD ADAS-cog MMSE 14-24, stable on AD drugs NTB + MRI / CSF MMSE ≥ 24, drug-naïve LipiDiDietMRS studyMEG study Souvenir IISouvenir IS-ConnectOpen Label NTB + EEG MMSE ≥ 20, drug-naïve WMS-r & ADAS-cog MMSE 20-26, drug-naïve Souvenir I received funding from NL STW Souvenir II receives funding from the NL Food & Nutrition Delta project, FND N°10003 LipiDiDiet is funded by the EU FP7 project LipiDiDiet, Grant Agreement N° NL-Enigma funded by NWO NIHC project, N° Safety + Compliance + NTB 31 P and 1 H-MRS MMSE ≥ 20, drug-naïve MEG + EEG +NTB MMSE ≥ 20, drug-naïve Mild AD Souvenaid Clinical Development 18 FDG-PET MMSE ≥ 20, drug-naïve NL-Enigma

27 Thank you!


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